Adipocytes are highly specialized cells that play a major role in energy homeostasis. Obesity affects >30% of the adult population in the United States and is a major risk factor for the development of Type 2 Diabetes mellitus (T2D). Obesity and insulin resistance can be linked to a breakdown in the cellular signaling and gene expression in adipocytes. Significant advances towards understanding metabolic disease states have been made by studying the function of signaling proteins and transcription factors that regulate adipocyte development and the modulation of gene expression in adipose tissue. Our research has focused on STATs (Signal Transducers and Activators of Transcription), a family of transcription factors whose activity is largely controlled by hormone-induced tyrosine phosphorylation. STAT5A promotes lipid deposition in preadipocytes, yet we have evidence to suggest the role of STAT5 proteins in mature adipocytes is to reduce lipid accumulation and insulin sensitivity. STATs can have cell-specific functions, and we hypothesize that STAT5 proteins in adipocytes contribute to systemic glucose and lipid metabolism and whole body energy expenditure by regulating fat cell glucose and lipid metabolism and adipokine production. Studies from the last funding cycle of this proposal have led us in new directions. We have data to demonstrate that STAT5A can physically associate with several proteins that comprise the pyruvate dehydrogenase complex (PDC). Collectively, our long term objective is to assess the functions of STAT5 proteins in mature adipocytes using in vitro and in vivo approaches and determine the functional relevance of the nuclear association of STAT5A and PDC. The first aim will be to perform metabolic analyses on a novel transgenic mouse with both STAT5 genes deleted specifically in adiponectin-expressing cells to assess the contribution of adipocyte STAT5 proteins to glucose and lipid metabolism. The second aim will be to determine the domains/residues of STAT5A that are required for its association with PDC-E2, and the impact of the STAT5/PDC interaction on modulation of STAT5-target gene expression. We propose that adipocyte STAT5 proteins are important in lipolysis and in the regulation of genes involved in lipid and glucose metabolism. We predict that loss of adipocyte STAT5 will have prominent metabolic effects in vivo including alterations in adipocyte lipolysis and systemic changes in insulin sensitivity.